Ethers of O-Desmethyl venlafaxine

ABSTRACT

This invention provides O-α-acyloxyalkyl ethers of the venlafaxine metabolite 4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol, represented by Formula (I):  
                 
 
     wherein:  
     the configuration at the steriogenic center (*) may be R, S, or RS (the racemate);  
     R 1  is selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 3 -C 6  cycloalkyl, or the moiety:  
                 
 
     R 2  is selected from H, or C 1 -C 6  alkyl; or,  
     R 1  and R 2  may be concatenated such that  
                 
 
      form a moiety having formula (b):  
                 
 
     R3 is selected from H or C 1 -C 6  alkyl; and  
     R4 and R5 are independently selected from H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  thioalkoxy, —CN, —OH, —CF 3 , —OCF 3 , halogen, —NH 2 , —NO 2 , or mono or dialkylamino wherein each alkyl group has 1 to 6 carbon atoms, or pharmaceutically acceptable salts or hydrates thereof, R, S, or RS forms thereof; as well as pharmaceutical compositions and methods treating central nervous system disorders.

FIELD OF THE INVENTION

[0001] This invention provides O-α-acyloxyalkyl ethers of4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol, as well aspharmaceutical compositions and uses thereof.

BACKGROUND OF THE INVENTION

[0002] Various patents and literature references describe the biologicalactivities of venlafaxine, and its salts and analogs. Venlafaxinehydrochloride tablets are marketed by Wyeth-Ayerst Laboratories asEFFEXOR.

[0003] The absolute configuration of the (+) enantiomer of venlafaxinewas established as S by a single crystal X-ray analysis of thehydrobromide salt and the anomalous dispersion technique (Yardley etal., J. Med. Chem., 1990, 33, 2899).

[0004] (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanoland its metabolites1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol and1-[1-(4-methoxyphenyl)-2-(methylamino)ethyl]cyclohexanol are disclosedand claimed in U.S. Pat. No. 4,535,186 (Husbands et al.). U.S. Pat. No.5,530,013 (Husbands et al.) claims the use of venlafaxine in theinducement of cognition enhancement. U.S. Pat. No. 5,506,270 (Upton etal.) claims venlafaxine's use in methods of treating hypothalamicamenorrhea in non-depressed women.

[0005] U.S. Pat. Nos. 5,788,986 (Dodman) and 5,554,383 (Dodman) teachesand claims the use of serotonin reuptake inhibitors in modifying thebehavior of dogs.

DETAILED DESCRIPTION OF THE INVENTION

[0006] This invention provides pharmaceutically active O-α-acyloxyalkylethers of the venlafaxine metabolite4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol (“O-Desmethylvenlafaxine” or “ODV”) having the structural formula I

[0007] wherein

[0008] the configuration at the steriogenic center (*) may be R, S, orRS (the racemate);

[0009] R₁ is selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl,or the moiety:

[0010] R₂ is selected from H, or C₁-C₆ alkyl; or,

[0011] R₁ and R₂ may be concatenated such that

[0012]  form a moiety having formula (b):

[0013] R3 is selected from H or C₁-C₆ alkyl; and

[0014] R4 and R5 are independently selected from H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, —CN, —OH, —CF₃, —OCF₃,halogen, —NH₂, —NO₂, or —N(CH₃)₂, or pharmaceutically acceptable saltsor hydrates thereof.

[0015] In some preferred embodiments of the present invention R1 ist-butyl, methoxy, or isobenzofuranone.

[0016] In other preferred embodiments of the invention R2 is C1-C3 alkyland in still more preferred embodiments of the invention R2 is methyl.

[0017] Specific examples of compounds of Formula I include:

[0018] {4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methylpivalate;

[0019]1-{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}ethylpropionate; and

[0020]3-{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}-2-benzofuran-1(3H)-one.

[0021] Particularly, this invention provides compounds and/orcompositions of both the O-α-acyloxyalkyl R-ether of Formula I and theO-α-acyloxyalkyl S-ether of Formula I, both being substantially free ofthe other. In addition, the invention provides the O-α-acyloxyalkylRS-ether of 4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]-phenol ofFormula I.

[0022] Substantially free, as used herein means the compound orcomposition is made up of significantly greater proportion of thedesired isomer than of the optical antipode. In a preferred embodimentof the invention, “substantially free” means that the compound orcomposition is made up of at least about 90% of the desired isomer andabout 10% or less of the optical antipode. In still more preferredembodiments of the present invention, the compound or composition ismade up of at least about 95% of the desired isomer and about 5% or lessof the optical antipode. In yet further embodiments of the presentinvention the compound or composition is made up of at least about 99%of the desired isomer and about 1% or less of the optical antipode.Preferably the characterized or separated enantiomer will exhibitphysical properties of a fully characterized compound, i.e. a uniformmelting point and a uniform rotation of plane-polarized light in apolarimeter. Most preferably, the enantiomers will be recrystallized toanalytical purity.

[0023] C₁-C₆ alkyl as used herein, such as in the definition of R₁,includes straight, branched chain alkyl groups within the specifiedrange of carbon atoms.

[0024] Halogen, as used herein refers to chlorine, bromine, iodine andfluorine.

[0025] Pharmaceutically acceptable salts refer to salts prepared frompharmaceutically acceptable acids, including inorganic acids and organicacids, such as, but not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, mitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic and the like.

[0026] Compounds of the invention are readily prepared by methods knownin the art, for instance, as described by Bodor, et al., J. Org.Chem.(48) 5280-5284 (1983).

[0027] The appropriate R-, S-, or(R/S)-4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol is reactedwith the appropriate O-α-acyloxyalkyl halide (examples:pivaloyloxymethyl chloride, 3-bromophthalide, iodomethyl pivalate)(Scheme Ia) or (acyloxy)benzyl α-halide (Scheme Ib) in an inert solvent(acetonitrile, tetrahydrofuran, dimethylformamide) in the presence of analkali metal carbonate (sodium or potassium carbonate) or transitionmetal carbonate (silver carbonate) in accordance with Schemes Ia and Ib.

[0028] wherein R₁ is selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆cycloalkyl, or the moiety:

[0029] R₂ is selected from H, or C₁-C₆ alkyl;

[0030] or R² and R³ are concatenated to form a moiety having formula(b);

[0031] R3 is selected from H or C₁-C₆ alkyl; and

[0032] R4 and R5 are independently selected from H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, —CN, —OH, —CF₃, —OCF₃,halogen, —NH₂, —NO₂, or mono or dialkylamino wherein each alkyl grouphas 1 to 6 carbon atoms.

[0033] In some preferred embodiments of the invention increased yieldmay be obtained by reacting the appropriate R-, S-, or(R/S)-4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol with theappropriate O-α-acyloxyalkyliodide in an inert solvent (acetonitrile,tetrahydrofuran, dimethylformamide) in the presence of alkali metalcarbonate such as potassium carbonate, or transition metal carbonatesuch as silver carbonate. Most preferred is the use ofO-α-acyloxyalkyliodide in the presence of silver carbonate at lowtemperatures in the range of approximately 0-5° C.

[0034] In a minor modification, compounds of formula I wherein R1 and R2are concatenated to form

[0035] and one or both of R₄ and R₅ are NH₂, can be obtained bycatalytic reductions, such as with palladium catalysts, fromcorresponding analogs wherein R₄ or R₅ are NO₂.

[0036] Racemic1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol can beproduced as described in Example 26 of U.S. Pat. No. 4,535,186 (Husbandset al.), which is incorporated herein by reference. It will beunderstood that the enantiomers may be separated from each other bystandard resolution techniques known in the art.

[0037] Alternatively, these R and S enantiomers may be obtained byO-demethylation of the separated enantiomers of venlafaxine using eitherboron tribromide or ethane thiol anion.

[0038] O-α-acyloxyalkyl ethers of Formula I and their pharmaceuticallyuseful salts and hydrates are useful for the biological andpharmacological activities for which venlafaxine and its salts are knownin the art. These O-α-acyloxyalkyl ethers may be used in treating orinhibiting central nervous system disorders, including depression,(including but not limited to major depressive disorder, biopolardisorder, and dysthymia), fibromyalgia, anxiety, panic disorder,agoraphobia, post-traumatic stress disorder, premenstrual dysphoricdisorder (also known as pre-menstrual syndrome), attention deficitdisorder (with and without hyperactivity), obsessive compulsive disorder(including trichotillomania), social anxiety disorder, generalizedanxiety disorder, autism, schizophrenia, obesity, anorexia nervosa,bulimia nervosa, Gilles de la Tourette Syndrome, vasomotor flushing,cocaine and alcohol addiction, sexual dysfunction (including prematureejaculation), borderline personality disorder, chronic fatigue syndrome,urinary incontinence, pain (including but not limited to migraine,chronic back pain, phantom limb pain, central pain, neuropathic painsuch as diabetic neuropathy and postherpetic neuropathy), Raynaud'ssyndrome, and others. These compounds are also useful in the inducementof cognition enhancement and in regimens for cessation of smoking orother tobacco uses.

[0039] This invention also includes methods of treating, preventing,inhibiting or alleviating each of the maladies listed above in a mammal,preferably in a human, the methods comprising providing apharmaceutically effective amount of a compound of this invention to themammal in need thereof.

[0040] “Providing” as used herein with respect to providing a compoundor substance covered by the invention, means either directlyadministering such a compound or substance, or administering a prodrug,derivative or analog which forms an equivalent amount of the compound orsubstance within the body.

[0041] A pharmaceutically effective dose will include those doses whichprovide the relief or prevention sought for the malady in question. Thecompounds of this invention may be provided in the dosages andpharmaceutical formulations known in the art as useful for venlafaxinehydrochloride (such as those doses known for the venlafaxinehydrochloride products marketed by Wyeth-Ayerst Laboratories under theEffexor® trademark). It will be understood that the initial dose,increases therefrom and final daily administration will be determined bya medical professional considering the needs and conditions for eachrecipient. For instance, a daily dose for an adult human may be fromabout 75 mg to about 450 mg per day, preferably between about 75 andabout 225 mg per day. An initial dose of 75 mg per day may beadministered, with increases as determined by a medical professional.

[0042] This invention also includes pharmaceutical compositionscomprising a pharmaceutically effective amount of a compound of thisinvention and one or more pharmaceutically acceptable carriers orexcipients. A preferred method of administration includes the use of thepresent compounds in extended release formulations of the type describedin published PCT application WO 99/22724 (Sherman et al.), which isincorporated herein by reference.

[0043] The present invention is exemplified, but not limited by, thefollowing specific examples.

EXAMPLE 1 {4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methyl pivalate

[0044]

[0045] 4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol (1 g,3.79 mmol), chloromethyl pivalate (0.75 g, 5 mmol), anhydrous K₂CO₃ (0.7g, 5 mmol) and KI (75 mg, 0.5 mmol) were stirred in acetonitrile (50 mL)and refluxed overnight. The solvent was evaporated and the residue waspartitioned between ethyl acetate and water. The ethyl acetate was dried(MgSO₄) and evaporated to give the title compound as a minor component.

[0046] IR (KBr) 1758 cm⁻¹.

[0047] MS(+)FAB[M+H]⁺378.3 calcd. For C₂₂H₃₅NO₄ 377.

EXAMPLE 2{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methylpivalate

[0048]

[0049] To a solution of ODV (2.0 g, 7.6 mmol) and silver carbonate (8.4g, 30.4 mmol) in acetonitrile (60 mL) at 0° C. was added a solution ofiodomethyl pivalate (prepared as described by Bodor, et al., J. Org.Chem. 1983, 48, 5280-5284.) (3.4 g, 14.0 mmol) in acetonitrile (100 mL)dropwise over 4 hr. The reaction mixture was filtered throughdiatomaceous earth (CELITE, Celite Corporation, Lompoc, Calif.), thenabsorbed onto a activated magnesium silicate (60-100 mesh) (FLORISIL,U.S. Silica Company), and purified by column chromatography (FLORISIL,ethyl acetate:acetonitrile 9:1) to afford the title compound (0.87 g,45%, based on 68% conversion) as a yellow tinted semi-solid: ¹H NMR(CD₃CN) δ0.78-1.0 (m, 2H), 1.19 (s, 9H), 1.15-1.35 (m, 4H), 1.4-1.7 (m,4H), 2.2 (s, 6H), 2.25 (dd, J=11.2, 4.5 Hz, 1H), 2.94 (dd, J=11.2, 4.5Hz, 1H), 3.22 (t, J=11.2 Hz, 1H), 5.7 (s, 2H), 6.95 (d, J=8.7 Hz, 1H),7.13 (d, J=8.7 Hz, 1H); ¹³C-NMR (CD₃CN) δ22.22, 22.44, 26.91, 27.10 (t),32.83, 38.78 (t), 39.55 (s), 45.71 (q), 52.58, 61.74, 74.45 (d), 86.78(t), 116.54, 131.48 (d), 136.68, 156.44, 178.05 (s); MS (ESI) m/z 378(M+H)⁺; further characterized as the maleate salt. Anal.(C₂₆H₃₉NO₈−0.25H₂O) Calc: C, 62.69; H, 7.99; N, 2.81; Found: C, 62.68;H, 7.68; N, 2.65.

[0050] The celite cake was taken up in brine and extracted with ethylacetate. Evaporation of the solvent affords 0.65 g (33%) recovered ODV.

EXAMPLE 3 4-[(1R)-2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenylpivalate

[0051]

[0052] To a solution of ODV (3.0 g, 11.4 mmol) and silver carbonate(12.6 g, 45.6 mmol) in acetonitrile (300 mL) at 0° C. was added asolution of iodomethyl pivalate (prepared as described by Bodor, et al.,J. Org. Chem. 1983, 48, 5280-5284.) (6.9 g, 28.5 mmol) in acetonitrile(40 mL) in eight equal portions over 16 hr. The reaction mixture wasfiltered through diatomaceous earth (CELITE, Celite Corporation, Lompoc,Calif.), then absorbed onto activated magnesium silicate (60-100 mesh)(FLORISIL, U.S. Silica Company) and purified by column chromatography(FLORISIL, ethyl acetate:acetonitrile 9:1) to afford the title compound(1.15 g, 39%, based on 60% conversion) as a white foam: ¹H NMR (CD₃CN)δ0.78-1.0 (m, 2H), 1.19 (s, 9H), 1.15-1.35 (m, 4H), 1.4-1.7 (m, 4H), 2.2(s, 6H), 2.25 (dd, J=11.2, 4.5 Hz, 1H), 2.94 (dd, J=11.2, 4.5 Hz, 1H),3.22 (t, J=11.2 Hz, 1H), 5.7 (s, 2H), 6.95 (d, J=8.7 Hz, 1H), 7.13 (d,J=8.7 Hz, 1H); ¹³C-NMR (CD₃CN) δ22.22, 22.44, 26.91, 27.10 (t), 32.83,38.78 (t), 39.55 (s), 45.71 (q), 52.58, 61.74, 74.45 (d), 86.78 (t),116.54, 131.48 (d), 136.68, 156.44, 178.05 (s); [α]²⁰ _(D) −5.95° (c1.00, MeOH); MS (ESI) m/z 378 (M+H)+.

[0053] The CELITE cake was taken up in brine and extracted with ethylacetate. Evaporation of the solvent affords 1.2 g (40%) recovered ODV.

EXAMPLE 4 4-[(1S)-2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenylpivalate

[0054]

[0055] To a solution of ODV (4.0 g, 15.2 mmol) and silver carbonate(16.8 g, 60.8 mmol) in acetonitrile (400 mL) at 0° C. was added asolution of iodomethyl pivalate (prepared as described by Bodor, et al.,J. Org. Chem. 1983, 48, 5280-5284.) (8.3 g, 34.3 mmol) in acetonitrile(150 mL) over a 9 hr period. The reaction mixture was filtered throughdiatomaceous earth (CELITE, Celite Corporation, Lompoc, Calif.), thenabsorbed onto activated magnesium silicate (60-100 mesh) (FLORISIL, U.S.Silica Company), and purified by column chromatography (FLORISIL, ethylacetate:acetonitrile 9:1) to afford the title compound (1.58 g, 48%,based on 57% conversion) as a clear viscous oil: ¹H NMR (CD₃CN)δ0.78-1.0 (m, 2H), 1.19 (s, 9H), 1.15-1.35 (m, 4H), 1.4-1.7 (m, 4H), 2.2(s, 6H), 2.25 (dd, J=11.2, 4.5 Hz, 1H), 2.94 (dd, J=11.2, 4.5 Hz, 1H),3.22 (t, J=11.2 Hz, 1H), 5.7 (s, 2H), 6.95 (d, J=8.7 Hz, 1H), 7.13 (d,J=8.7 Hz, 1H); ¹³C-NMR (CD₃CN) δ22.22, 22.44, 26.91, 27.10 (t), 32.83,38.78 (t), 39.55 (s), 45.71 (q), 52.58, 61.74, 74.45 (d), 86.78 (t),116.54, 131.48 (d), 136.68, 156.44, 178.05 (s); [α]²⁰ _(D) +7.23° (c1.00, MeOH); MS (ESI) m/z 378 (M+H)+.

[0056] The CELITE cake was taken up in brine and extracted with ethylacetate. Evaporation of the solvent affords 1.7 g (43%) recovered ODV.

EXAMPLE 5{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methylpivalate Maleate salt

[0057]

[0058] To a solution of{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methylpivalate (0.032 g, 0.085 mmol) prepared as described in Example 1, inTHF (1.0 mL) at RT was added a solution of maleic acid (0.007 g, 0.06mmol) in THF (1.0 mL). The mixture was warmed and diluted with hexane.The solution was cooled and the resulting crystals filtered off givingthe desired maleate salt as a white solid: mp 112-113° C., ¹H NMR(DMSO-d₆) δ0.9-1.6 (m, 10H), 1.13 (s, 9H), 2.7 (br.s, 6H), 2.97 (m, 1H),3.55 (m, 2H), 4.59 (br.s, 1H), 5.78 (s, 2H), 6.02 (s, 2H), 7.03 (d,J=8.6 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 8.4 (br.s, 1H); MS (ESI) m/z 378(M+H)+; (C₂₆H₃₉NO₈−0.25H₂O) Calc: C, 62.69; H, 7.99; N, 2.81, Found: C,62.68; H, 7.68; N, 2.65.

What is claimed:
 1. A compound of the Formula (I):

wherein the configuration at the steriogenic center (*) may be R, S, orRS (the racemate); R₁ is selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆cycloalkyl, or the moiety:

R₂ is selected from H, or C₁-C₆ alkyl; or R₁ and R₂ may be concatenatedsuch that

 form a moiety having formula (b):

R3 is selected from H or C₁-C₆ alkyl; and R4 and R5 are independentlyselected from H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆thioalkoxy, —CN, —OH, —CF₃, —OCF₃, halogen, —NH₂, —NO₂, or mono ordialkylamino wherein each alkyl group has 1 to 6 carbon atoms, orpharmaceutically acceptable salts or hydrates thereof.
 2. A compound ofclaim 1 wherein R1 is C₁-C₆ alkyl or C₁-C₆ alkoxy.
 3. A compound ofclaim 1 wherein R2 is C₁-C₆ alkyl.
 4. A compound of claim 1 wherein R1and R2 are concatenated such that

form a moiety having formula (b):

and R4 and R5 are hydrogen.
 5. A compound of claim 1 which is{4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methylpivalate, or a pharmaceutically acceptable salt or hydrate thereof.
 6. Acompound of claim 1 which is1-{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}ethylpropionate, or a pharmaceutically acceptable salt or hydrate thereof.


7. A compound of claim 1 which is3-{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}-2-benzofuran-1(3H)-one,or a pharmaceutically acceptable salt or hydrate thereof.
 8. Apharmaceutical composition comprising a pharmaceutically effectiveamount of a compound of Formula I

wherein: the configuration at the steriogenic center (*) may be R, S, orRS; R₁ is selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, orthe moiety:

R₂ is selected from H, or C₁-C₆ alkyl; or, R₁ and R₂ may be concatenatedsuch that

 form a moiety having formula (b):

R3 is selected from H or C₁-C₆ alkyl; and R4 and R5 are independentlyselected from H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆thioalkoxy, —CN, —OH, —CF₃, —OCF₃, halogen, —NH₂, —NO₂, or mono ordialkylamino wherein each alkyl group has 1 to 6 carbon atoms, orpharmaceutically acceptable salts or hydrates thereof; and apharmaceutically acceptable carrier or excipient.
 9. A method oftreating disorders of the central nervous system in a mammal, the methodcomprising providing to a mammal in need thereof a pharmaceuticallyeffective amount of a compound of Formula I

wherein: the configuration at the steriogenic center (*) may be R, S, orRS; R₁ is selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, orthe moiety:

R₂ is selected from H, or C₁-C₆ alkyl; or, R₁ and R₂ may be concatenatedsuch that

 form a moiety having formula (b):

R3 is selected from H or C₁-C₆ alkyl; and R4 and R5 are independentlyselected from H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆thioalkoxy, —CN, —OH, —CF₃, —OCF₃, halogen, —NH₂, —NO₂, or mono ordialkylamino wherein each alkyl group has 1 to 6 carbon atoms, or apharmaceutically acceptable salt or hydrate thereof.
 10. The method ofclaim 9 wherein the central nervous system disorder is depression. 11.The method of claim 9 wherein the central nervous system disorder isgeneralized anxiety disorder.
 12. The method of claim 9 wherein thecentral nervous system disorder is panic disorder.
 13. The method ofclaim 9 wherein the central nervous system disorder is post traumaticstress disorder.
 14. The method of claim 9 wherein the central nervoussystem disorder is attention deficit disorder, with and withouthyperactivity.
 15. The method of claim 9 wherein the central nervoussystem disorder is anxiety.
 16. The method of claim 9 wherein thecentral nervous system disorder is schizophrenia.
 17. The method ofclaim 9 wherein the central nervous system disorder is cocaine andalcohol addiction.
 18. The method of claim 9 wherein the central nervoussystem disorder is premenstrual dysphoric disorder.
 19. The method ofclaim 9 wherein the central nervous system disorder is autism.
 20. Themethod of claim 9 wherein the central nervous system disorder isanorexia nervosa, bulimia nervosa, vasomotor flushing, and chronicfatigue syndrome.
 21. The method of claim 9 wherein the central nervoussystem disorder is urinary incontinence.
 22. The method of claim 9wherein the central nervous system disorder is pain.
 23. The method ofclaim 9 wherein the central nervous system disorder is sexualdysfunction.
 24. A method of enhancing cognition in a mammal, the methodcomprising providing to a mammal in need thereof a pharmaceuticallyeffective amount of a compound of Formula I

wherein: the configuration at the steriogenic center (*) may be R, S, orRS; R₁ is selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, orthe moiety:

R₂ is selected from H, or C₁-C₆ alkyl; or, R₁ and R₂ may be concatenatedsuch that

 form a moiety having formula (b):

R3 is selected from H or C₁-C₆ alkyl; and R4 and R5 are independentlyselected from H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆thioalkoxy, —CN, —OH, —CF₃, —OCF₃, halogen, —NH₂, —NO₂, or mono ordialkylamino wherein each alkyl group has 1 to 6 carbon atoms, or apharmaceutically acceptable salt or hydrate thereof.